A short and efficient synthesis of bridgehead mono-and dideuteriated tropinones

Article abstract of DOI:10.1002/ejoc.200901018

Studies of the biosynthesis and degradation of alkaloids of the tropane class require substrates isotopically-labelled at specific positions. To investigate the mechanism of the enzyme reactions involved in the hydroxylation of the bridgehead position(s), compounds deuteriated at this position are needed. An efficient synthesis of 1,5-dideuterio-and racemic 1-deuteriotropinone is described in which high levels of deuterium are incorporated from the corresponding di-and mono-labelled 2,5-dibutoxytetrahydrofuran.

Full text of DOI:10.1002/ejoc.200901018

FULL PAPER
DOI: 10.1002/ejoc.200901018
A Short and Efficient Synthesis of Bridgehead Mono- and Dideuteriated
Tropinones
[
a]
[a]
[a]
Anaïs Fournial, Tsiresy Ranaivondrambola, Monique Mathé-Allainmat,
[a]
[a]
Richard J. Robins, and Jacques Lebreton*
Keywords: Alkaloids / Tropane / Deuterium / Isotopic labeling
Studies of the biosynthesis and degradation of alkaloids of
the tropane class require substrates isotopically-labelled at
specific positions. To investigate the mechanism of the en-
zyme reactions involved in the hydroxylation of the bridge-
head position(s), compounds deuteriated at this position are
needed. An efficient synthesis of 1,5-dideuterio- and racemic
1-deuteriotropinone is described in which high levels of deu-
terium are incorporated from the corresponding di- and
mono-labelled 2,5-dibutoxytetrahydrofuran.
Introduction
The tropane alkaloids, which all have the 8-azabicyclo-
[
3.2.1]octane core, are found in plants of the Solanaceae,
[1]
Erythroxylaceae and Convolvulaceae families. A number
of these alkaloids, notably hyoscyamine (1), scopolamine (2)
and cocaine (3) (Figure 1), have received considerable atten-
tion due to their important biological properties and their
various medicinal uses. A sub-group, the calystegines [e.g.,
calystegine A (4), Figure 1], are known to be powerful gly-
3
cosidase inhibitors.[ These polyhydroxylated nortropane
2]
alkaloids, derived from tropinone (5) by N-demethylation,
[
3]
have been isolated from a number of plant species. They
are characterised by a 3-exo-hydroxy group [in contrast to
the 3-endo of, for example, hyoscyamine (1)] and all have a
hydroxy function at the bridge position of the nortropane
skeleton. Indeed, calystegines can also be hydroxylated at
the 2-, 4-, 6- or 7-position. To date, the mechanism by which
Figure 1. Structures of (–)-hyoscyamine (1), (–)-scopolamine (2),
(
3
–)-cocaine (3) and (–)-calystegine A (4).
Furthermore, and especially in view of their importance
these hydroxy groups are introduced is unknown. The only as bioactive compounds, the degradation of tropane alka-
enzyme that has been reported to hydroxylate a tropane al- loids has received surprisingly little attention. It has been
kaloid is the enzyme that hydroxylates the 7-position of hy- demonstrated in humans that the degradation of these alka-
oscyamine (1) in the first step of the formation of the 6,7- loids involves P450 cytochrome oxidase and is initiated by
exo-epoxide of scopolamine (2).[ This enzyme belongs to N-demethylation. However, the best-studied system is a
4]
[5]
the iron ascorbate class and not to the more commonly en- Pseudomonas bacterium, which exploits tropine alkaloids as
[
6]
countered and better described cytochrome P450 oxidases. the sole source of carbon and nitrogen. In this organism,
Thus, it is of general interest to investigate further the degradation of tropane bases is also initiated by N-demeth-
mechanism(s) of the enzymes responsible for the hydroxyla- ylation followed by cleavage of the N–C1 or N–C5 bond
tion at other positions.
and then deamination to recover the nitrogen and catabo-
lism of the carbon skeleton. Critically, it is implicit that the
[
a] Université de Nantes, CNRS, Laboratoire CEISAM-UMR cleavage reaction involves hydroxylation of the 1- or 5-posi-
6
2
230, Faculté des Sciences et des Techniques,
tion, although this remains to be rigorously proven. Never-
theless, this micro-organism provides a good system in
which to carry out mechanistic studies both of the N-de-
methylation and of the hydroxylation/ring-opening steps of
tropane alkaloid degradation. This objective requires the
rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France
Fax: +33-2-51125562
E-mail: jacques.lebreton@univ-nantes.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901018.
152
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 152–156

Synthesis of Bridgehead Mono- and Dideuteriated Tropinones
synthesis of several tracer molecules, including bridge-lab- oxytetrahydrofurans are an important class of intermedi-
elled di- and mono-deuteriated tropinones 6 and (Ϯ)-7, ates, mainly for the preparation of various pyrrole deriva-
[
16]
respectively (Figure 2). Only a few ring-deuteriated tro- tives,
panone derivatives have been described in the literature
to the best of our knowledge only two different
routes to these compounds have been reported in the litera-
and, to the best of our knowledge, none have been labelled ture. In both approaches from furans in alcoholic solution,
[
7]
at the bridgehead carbon positions.
the unstable 2,5-dialkoxy-2,5-dihydrofurans are hydroge-
nated after being obtained either by the electrochemical
[
17]
method of Clausson–Kass
or by oxidative alk-
[
18]
oxylation with bromine or chloride. The key elements to
our success in generating deuteriated 2,5-dialkoxytetra-
hydrofurans A and B were, first, the introduction of deute-
rium from a low-cost commercially available deuteriated
reagent and, secondly, the use of higher-mass alkyl groups
to decrease their volatility, thus facilitating their work-up
and purification.
2
2
Figure 2. Structures of tropinone (5), [1,5- H ]tropinone (6) and
2
(
Ϯ)-[1- H]tropinone (7).
In view of the unique core unit of these natural products,
it is not surprising that they have emerged as a crucial scaf-
fold in a wide variety of analogues with various pharmaco-
[
8]
logical properties. The tropanes and their congeners have
been the target of many syntheses since Willstätter’s synthe-
sis of tropinone (5; see Figure 2) in 1903.[ Robinson’s land-
mark synthesis of tropinone (5) by a double-Mannich three-
component reaction from succinaldehyde, methylamine and
the calcium salt of acetone-1,3-dicarboxylic acid, published
in 1917, can be regarded as one of the first multi-compo-
nent reactions and is still one of the most effective ways to
synthesise the tropane core structure.[ A major improve-
ment in this procedure was the use of 2,5-dimethoxytetra-
hydrofuran (8) as a precursor of succinaldehyde.[ Since
this pioneering work of Robinson, a variety of synthetic
approaches for the preparation of tropine derivatives have
9]
Figure 3. Intermediates of the Robinson (8) and Mikami and
Ohmura (9) syntheses and the deuteriated 2,5-dialkoxytetra-
hydrofurans A and B corresponding to 8.
10]
11]
Results and Discussion
On the basis of these requirements, an obvious synthetic
been described in the literature. Tropinone (5) can be pre- strategy (Scheme 1) to reach our first labelled target 10 was
pared by the simple addition of methylamine to cyclohep- to exploit the well-described chemistry of the Weinreb di-
[
12]
[13]
[19]
tadienone
or by [4+3] cycloaddition
of N-protected amides. Thus, reducing the Weinreb diamide 11 with Li-
pyrroles and tetrabromoacetone. An efficient one-pot syn- AlD (98 atom-% D) and treatment of the reaction mixture
4
thesis of the tropane alkaloid based on tandem (domino) directly with an acidic aqueous solution of BuOH should
ene-type reactions of siloxyallylsilane with N-methoxycar- afford the di-deuteriated 2,5-dibutoxytetrahydrofuran
[
20]
bonyl-2,5-dimethoxypyrrolidine (9) without acidification (10), which is less volatile than the dimethoxy derivative
and decarboxylation was published by Mikami and 8.
[
14]
Ohmura.
The selective introduction of a labelled atom into organic
structures offers a continuing challenge to organic chemists
due in part to the relatively small number of enriched start-
ing materials and/or reagents that are commercially avail-
able, placing considerable limitations on the choice of strat-
egy. An examination of the published syntheses of trop-
inone (5) showed many of them not to be compatible with
Scheme 1. Retrosynthetic scheme for the preparation of 2,5-dibut-
oxytetrahydrofuran (10).
The Weinreb diamide 11 was prepared from succinyl
an efficient and selective introduction of deuterium into the chloride as described previously in the literature.[21] With
desired positions. For example, to follow the work of Mi- this substrate in hand, reduction with LiAlD followed by
4
kami and Ohmura,[ the preparation of the required de- treatment with BuOH was then investigated under various
uteriated N-methoxycarbonyl-2,5-dimethoxypyrrolidine de- conditions. The best result was obtained when the Weinreb
rivatives by anodic dimethoxylation of the corresponding diamide 11 was treated at 0 °C in THF with a slight excess
14]
carbamate of pyrrolidine was not obvious.[15] In this con- of LiAlD followed by the slow addition of an aqueous
4
text, we felt that Robinson’s synthesis offered the most at- solution of BuOH (Scheme 2). Under these conditions, the
tractive access to our targets. It was clear that the success desired labelled 2,5-dibutoxytetrahydrofuran (10) was iso-
of this approach would be dependent on the preparation of lated in 55% crude yield for this one-pot two-step process.
the corresponding di- and mono-labelled 2,5-dialkoxytetra- This material was suitable for use in the Robinson synthesis
hydrofurans A and B (Figure 3). Even though the 2,5-dialk- without further purification. Note that, although with both
Eur. J. Org. Chem. 2010, 152–156
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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153

J. Lebreton et al.
FULL PAPER
2,5-dibutoxytetrahydrofurans 10 and 14 the trans and cis relation between the HRMS values, 141.1138 and 141.1137,
isomers could be isolated in pure form after purification on calculated and found, respectively, confirms that the deute-
silica gel chromatography, a slow isomerisation occurred to rium is only present at the bridge carbon position. In all
1
afford a cis/trans mixture (see the NMR spectra in the Sup- other respects, the H NMR spectrum is identical to that
porting Information). Careful monitoring of the hydrolysis of authentic tropinone taking into account the altered cou-
of 2,5-dibutoxytetrahydrofuran (10) by TLC ensured that pling pattern due to the presence of the bridgehead deute-
the formation of succinaldehyde[ was complete before the rium.
22]
addition of this solution to a mixture of methylamine and
acetone-1,3-dicarboxylic acid following the Robinson pro-
tocol. The pure, doubly labelled tropinone 6 was isolated in
50% crude yield. The absence of proton signals from the
C-1 and C-5 bridge positions is immediately apparent by
1
inspection of the H NMR spectrum (see the Supporting
Information), which indicates a high level of deuteriation
2
1
[23]
(
[ H]/[ H] Ն 95:5).
deuteriated, as evidenced by a comparison of the calculated
142.1201) and measured HRMS values (142.1200). In all
In contrast, no other positions are
(
1
other respects, the H NMR spectrum is identical to that
of authentic tropinone, taking into account the altered cou-
3 2 2
pling pattern due to the presence of the bridgehead deute- Scheme 3. Reagents and conditions: (a) O , CH Cl , –78 °C, then
Me
2
S; (b) (EtO)
3
CH, EtOH, cat. APTS, 6 h, room temp., 30% for
, THF, 0 °C, 30 min, then BuOH/H
25:1) followed by 6  HCl, 3 h, room temp., 77% (crude); (d) 0.3 
rium atoms.
the two steps; (c) LiAlD
(
4
2
O
2 2
HCl, H O, 100 °C, 2 h, then addition to a solution of MeNH ,
acetone-1,3-dicarboxylic acid, AcONa, concentrated aqueous HCl,
O, 2 h, 50 °C, 62%.
H
2
4
Scheme 2. Reagents and conditions: (a) LiAlD , THF, 0 °C,
Conclusions
3
0 min, then BuOH/H
b) 0.3  HCl, H O, 100 °C, 2 h, then addition to a solution of
acetone-1,3-dicarboxylic acid, AcONa, concentrated
O, 2 h, 50 °C, 50 %.
2
O (25:1) followed by 6  HCl, 55% (crude);
(
2
We have reported herein a short practical synthesis of
labelled tropinone in which deuterium is incorporated in a
specific manner at the bridgehead carbons C-1 and C-5.
2
MeNH ,
aqueous HCl, H
2
For the preparation of the mono-deuteriated derivative Deuterium can be introduced at one position, or simulta-
(
Ϯ)-7 from the unsaturated Weinreb 12, the idea was to use neously at both. The key to the approach is the preparation
ozonolysis followed by protection of the resulting aldehyde of appropriately labelled deuteriated 2,5-dibutoxytetrahyd-
as the corresponding acetal in order to differentiate the two rofurans 10 and 14 in which the introduction of the heavier
potential aldehyde functions, leading to the reduction of the alkyl substituent markedly improves the overall yield while
amide with LiAlD , as outlined in Scheme 3. Ozonolysis diminishing volatility. This approach is scalable and avoids
4
of the unsaturated Weinreb amide 12, prepared from the the use of costly deuteriated reagents. Furthermore, modifi-
[
26]
commercially available carboxylic acid, was carried out in cations such as their reduction to tropine and the synthe-
[
27]
CH Cl solution at –78 °C followed by reduction of the in- sis of the corresponding biologically active esters can be
2
2
termediate ozonide with Me S. After work-up, the crude achieved by using standard procedures. We can anticipate
2
aldehyde intermediate was treated with triethyl orthofor- that these deuteriotropinones will find application in a wide
[
24]
mate in ethanol in the presence of a catalytic amount of range of studies of the metabolism of tropane alkaloids,
[25]
APTS to afford the desired acetal 13 in 30% yield for the notably the calystegines, in studies of biologically active tro-
two steps after purification. This material 13 was reduced pane derivatives, and as substrates for probing the mecha-
with LiAlD and treated as described previously for 10 to nisms of tropine-metabolising enzymes.
4
afford the mono-deuteriated dibutoxytetrahydrofuran 14 in
7
7% crude yield. This material was sufficiently pure to be
Experimental Section
used directly in the Robinson synthesis under the same con-
ditions as those used for 6. The pure mono-labelled tropi-
none (Ϯ)-7 was isolated in 62% yield. As previously, there
was no evidence for either loss of deuterium or of deute-
rium being introduced elsewhere into the molecule. Thus,
2
Lithium aluminium deuteride (98 atom-% H) was purchased from
Acros Organics (www.acros.com).
N,NЈ-Dimethoxy-N,NЈ-dimethylsuccinimide (11): Triethylamine
(
18.1 mL, 129.9 mmol) was added slowly to a suspension of N,O-
dimethylhydroxylamine (6.3 g, 64.5 mmol) and succinyl chloride
5.0 g, 32.3 mmol) in CH Cl (80 mL) at 0 °C under nitrogen. After
mation), as would be predicted for a high level of mono- stirring for 2 h the solution was warmed to room temperature and
deuteriation at the C-1 position. Similarly, the excellent cor- then quenched with saturated aqueous NaHCO solution. The lay-
1
integration of the C-1/C-5 protons in the H NMR spec-
2
1
trum gives [ H]/[ H] Ն 98:2 (see the Supporting Infor-
(
2
2
3
154
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 152–156

Synthesis of Bridgehead Mono- and Dideuteriated Tropinones
ers were separated and the aqueous layer extracted with CH
2
Cl
2
ether as eluent). Evaporation of the appropriate fractions gave N-
methoxy-N-methylpent-4-enamide (3.54 g, 83% over two steps). H
1
(3ϫ30 mL). The organic layers were combined, washed with brine,
dried with MgSO
4
and evaporated under reduced pressure. The
NMR (300 MHz, CDCl
3
): δ = 2.33–2.39 (m, 2 H), 2.40–2.53 (m, 2
1
crude material (6.4 g) was used directly in the next step. H NMR
300 MHz, CDCl ): δ = 2.72 (s, 4 H), 3.13 (s, 6 H), 3.69 (s, 6
H) ppm. C NMR (75 MHz, CDCl ): δ = 26.2, 32.0, 61.0,
H), 3.16 (s, 3 H), 3.66 (s, 3 H), 4.91–5.11 (m, 2 H), 5.80–5.89 (m,
1
3
(
3
3
1 H) ppm. C NMR (75 MHz, CDCl ): δ = 28.3, 30.9, 31.9, 60.9,
13
3
114.8, 137.2, 173.5 ppm. HRMS (ESI): calcd. for C
7
H13NO
2
[M +
+
173.2 ppm.
H] 144.1025; found 144.1024.
2
[
3
2,5- H
2
]2,5-Dibutoxytetrahydrofuran
(10):
LiAlD
4
(1.37 g,
4,4-Diethoxy-N-methoxy-N-methylbutanamide (13): Ozone was
bubbled through a solution of N-methoxy-N-methyl-4-pentanam-
6.3 mmol) was added to a solution of N,NЈ-dimethoxy-N,NЈ-di-
methylsuccinimide (11; 2.50 g, 12.3 mmol) in THF (90 mL) at 0 °C.
ide (12; 1.7 g, 11.9 mmol) in CH
2 2
Cl (90 mL) at –78 °C until a blue
After stirring for 30 min at 0 °C, a mixture of n-butanol (300 mL) colour persisted. Then Me
2
S (8.7 mL, 118 mmol) was added and
and water (11.3 mL) was added slowly, followed by aqueous 6 
HCl (37.7 mL). After stirring at room temperature for 4 h, the mix-
the reaction mixture was stirred and warmed to room temperature
overnight. The resulting crude product was washed with brine and
the aqueous layer was extracted with diethyl ether (3ϫ50 mL). The
ture was washed with saturated NaHCO
3
solution and brine, and
dried with MgSO . The organic layer was filtered and the solvents
4
4
organic layers were combined, dried with MgSO and concentrated
evaporated. The crude material as a cis/trans mixture (1.49 g, 55%)
under reduced pressure. The crude aldehyde was used in the next
step without further purification. Triethyl orthoformate (1.7 mL,
10.1 mmol) and a catalytic amount of APTS (133 mg, 0.7 mmol)
was added to a solution of the aldehyde (1.02 g, 7.0 mmol) in etha-
nol (30 mL). After stirring for 6 h at room temperature the reaction
was used directly in the next step without further purification. An
2
analytical sample containing trans-[2,5- H
2
]2,5-dibutoxytetrahyd-
rofuran (10) as the major isomer was obtained by column
chromatography on silica gel (pure petroleum ether to 96:4 petro-
leum ether/diethyl ether as eluent). Evaporation of the appropriate
mixture was quenched with a saturated solution of NaHCO
aqueous layer was extracted with CH Cl (3ϫ30 mL). The organic
layers were combined, dried with MgSO and concentrated under
.3 Hz, 6 H), 1.26–1.40 (m, 4 H), 1.45–1.57 (m, 4 H), 1.70–1.82 (m, reduced pressure. The crude material (1.30 g) was purified by col-
3
. The
2
fractions gave [2,5- H
colourless liquid. H NMR (300 MHz, CDCl
2
]2,5-dibutoxytetrahydrofuran (10) as
a
2
2
1
3
): δ = 0.88 (t, J =
4
7
2
H), 2.04–2.10 (m, 2 H), 3.40 (td, J = 6.7, J = 9.4 Hz, 2 H), 3.65
umn chromatography on silica gel (80:20 to 35:65 petroleum ether/
diethyl ether as eluent). Evaporation of the appropriate fractions
13
3
(td, J = 6.7, J = 9.4 Hz, 2 H) ppm. C NMR (75 MHz, CDCl ):
δ = 13.8, 19.3, 30.1, 31.8, 67.4, 103.8 (JC-D = 34.4 Hz) ppm.
gave 4,4-diethoxy-N-methoxy-N-methylbutanamide (13; 840 mg,
1
30% over two steps) as a colourless liquid. H NMR (300 MHz,
2
[
1,5- H
2
]Tropinone (6): Aqueous 0.3  HCl (1.8 mL) was added to
3
CDCl ): δ = 1.16 (t, J = 7.0 Hz, 6 H), 1.91 (dt, J = 5.6, J = 7.5 Hz,
2
the previous crude [2,5- H
00 mg, 2.3 mmol) and the solution was heated at 100 °C for 2 h.
After cooling to 10 °C this mixture was added to a solution con-
taining water (2.2 mL), NaOAc (1.06 g, 12.9 mmol), MeNH
2
]2,5-dibutoxytetrahydrofuran (10;
2
3
H), 2.48 (t, J = 7.4 Hz, 2 H), 3.14 (s, 3 H), 3.39–3.52 (m, 2 H),
.60–3.72 (m, 2 H), 3.65 (s, 3 H), 4.52 (t, J = 5.5 Hz, 4 H) ppm.
C NMR (75 MHz, CDCl ): δ = 15.2, 26.7, 28.3, 32.1, 61.1, 61.3,
3
5
13
2
102.9, 174.0 ppm.
(322 µL, 40% aqueous solution, 3.6 mmol), conc. HCl (308 µL,
2
3.6 mmol) and acetone-1,3-dicarboxylic acid (540 mg, 3.6 mmol). [2- H]2,5-Dibutoxytetrahydrofuran
(14):
LiAlD
4
(206 mg,
The mixture was warmed at 50 °C for 2 h and then cooled to ambi-
ent temperature. A 2  NaOH solution was added to give pH 10.
After the addition and complete dissolution of NaCl (600 mg), the
4.9 mmol) was added to a solution of 4,4-diethoxy-N-methoxy-N-
methylbutanamide (13; 863 mg, 3.9 mmol) in THF (45 mL) at 0 °C.
After stirring for 30 min at 0 °C a solution of n-butanol (80 mL)
and water (2.9 mL) was added slowly followed by aqueous 6  HCl
(10.1 mL). The resulting mixture was stirred at room temperature
solution was extracted with CH
ganic layers were acidified with aqueous 0.1  HCl to give pH 2.
The acidified aqueous layer was extracted three times with CH Cl
The aqueous phase was basified with a 0.1  NaOH solution to
give pH 13 and then extracted with CH Cl . The combined organic
layer was concentrated under reduced pressure to give pure [1,5-
2 2
Cl (5ϫ5 mL). The combined or-
2
2
.
2 3
for 3 h and then washed with a solution of K CO until pH 7. The
organic layer was evaporated under reduced pressure to give crude
2
2
2
[2- H]2,5-dibutoxytetrahydrofuran (14; 655 mg, 77%) as a cis/trans
mixture, which was used directly in the next step without further
purification. An analytic sample containing trans-14 as the major
isomer was obtained by column chromatography on silica gel (pure
2
1
H
2
]tropinone (6; 160 mg, 50%) as a colourless oil. H NMR
400 MHz, CDCl ): δ = 1.54–1.62 (m, 2 H), 2.09 (d, J = 7.8 Hz, 2
H), 2.17 (d, J = 16.4 Hz, 2 H), 2.47 (s, 3 H), 2.67 (d, J = 15.7 Hz,
H) ppm. 13C NMR (100 MHz, CDCl
(
3
petroleum ether to 50:50 petroleum ether/diethyl ether as eluent).
2
2
3
): δ = 27.6, 38.2, 47.4, 60.4 Evaporation of the appropriate fractions gave [2- H]2,5-dibutoxy-
1
(
C
J
C-D
=
22.3 Hz), 209.5 ppm. HRMS (ESI): calcd. for
NO [M + H] 142.1201; found 142.1200.
tetrahydrofuran (14) as a colourless liquid. H NMR (300 MHz,
CDCl ): δ = 0.90 (t, J = 7.3 Hz, 6 H), 1.28–1.38 (m, 4 H), 1.47–
.58 (m, 4 H), 1.73–1.81 (m, 2 H), 2.06–2.12 (m, 2 H), 3.32–3.44
+
12
H
23
D
2
3
1
N-Methoxy-N-methylpent-4-enamide (12): 4-Pentenoic acid (3 g,
0.0 mmol) and SOCl (3.2 mL, 44.9 mmol) were heated at 60 °C
13
(
m, 2 H), 3.62–3.71 (m, 2 H), 5.15–5.19 (m, 1 H) ppm. C NMR
75 MHz, CDCl ): δ = 13.8, 19.2, 29.6, 31.0, 67.5, 103.8 (JC-D
4.4 Hz), 104.1 ppm.
3
2
(
3
3
=
for 5 h. Once cooled, the corresponding acid chloride was added
at 0 °C to a solution of N,O-dimethylhydroxylamine (4.38 g,
2
4
8
3
2
4.9 mmol) in CH
2
Cl
2
(150 mL). Then triethylamine (13 mL,
[1- H]Tropinone (7): Aqueous 0.3  HCl (1.8 mL) was added to the
2
9.9 mmol) was added dropwise over 15 min. After stirring for
0 min at 0 °C, the solution was warmed to room temperature over
h. The mixture was quenched with a saturated solution of
crude [2- H]2,5-dibutoxytetrahydrofuran (14; 250 mg, 1.15 mmol)
and heated at 100 °C for 2 h. After cooling to 10 °C, this mixture
was added to a solution containing water (1.1 mL), NaOAc
NaHCO
extracted with CH
washed with brine, dried with MgSO
duced pressure. The crude material was purified by column
chromatography (silica gel; 100 to 50:50 petroleum ether/diethyl
3
. The layers were separated and the aqueous layer was
Cl . The organic layers were combined and
and evaporated under re-
2
(528 mg, 6.44 mmol), MeNH (160 µL, 40% aqueous solution,
2
2
1.84 mmol), conc. HCl (153 µL, 1.84 mol) and acetone-1,3-dicar-
boxylic acid (268 mg, 1.84 mmol). The mixture was warmed at
50 °C for 2 h, cooled to ambient temperature and worked up as
4
2
2
described for [1,5- H
2
]tropinone (6) to give [1- H]tropinone (7;
Eur. J. Org. Chem. 2010, 152–156
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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155

J. Lebreton et al.
FULL PAPER
1
100 mg, 62%) as a colourless oil. H NMR (400 MHz, CDCl
3
): δ [9] R. Willstätter, Justus Liebigs Ann. Chem. 1903, 317, 204.
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3
Ritter, J. L. Speakman, M.-A. Williams, Org. Process Res. Dev.
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(
3
): δ = 27.6, 38.2, 47.5,
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1
6
+
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H21DNO [M + H] 141.1138; found 141.1137.
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1
13
this article): H and C NMR spectra of 6, 7, 10–14.
[
[
Acknowledgments
This program was supported financially by the Agence Nationale
de la Recherche (ANR), France (project ISOMODTS PCV_08-
[
[
[
320274). A. F. thanks the ANR for the financing of a post-doctoral
fellowship. We thank Virginie Silvestre (Laboratoire CEISAM-
UMR 6230) for assistance with NMR analyses and Carol Wriggles-
worth (Scientific English, Nantes, France) for linguistic assistance.
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[
[
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[
[
[
[
[
23] A small peak centred at around 3.48 ppm due to traces of ether
2
1
makes it impossible to evaluate the [ H]/[ H] ratio more accu-
rately (see the Supporting Information).
24] Note that direct treatment of the crude aldehyde in nBuOH in
the presence of APTS to yield the corresponding acetal is less
efficient.
25] This protected aldehyde 13 was found to be rather unstable,
particularly during purification on silica, even in the presence
of triethylamine.
1
994, 270, 35.
[
[
[
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Received: September 7, 2009
Published Online: November 26, 2009
156
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